An aldobionamide is defined herein as the amide of an aldobionic acid. The aldobionic acid is a sugar substance (e.g., any cyclic sugar) wherein the aldehyde group (generally found at the C.sub.1 position of the sugar) has been replaced by a carboxylic acid. Aldobionamides are based on compounds comprising more than one saccharide unit; they may be based on compounds comprising two saccharide units (e.g., lactobionamide or maltobionamide) or they may be based on compounds comprising more than two saccharide units as long as the polysaccharide has a terminal sugar unit with an aldehyde group available for oxidation.
The inventive compositions include antiplaque agents which are specific aldobionamides containing at least one .beta.-galactosidic linkage.
It is generally recognized that the development of dental plaque begins with the adhesion of bacteria to the teeth. Bacterial adhesion to tooth surfaces usually involves stereospecific interactions between cell surface binding proteins, referred to as adhesins, and cognate structures which form binding sites either in salivary pellicle, or on the surfaces of other bacteria resident in plaque, or in the extracellular plaque matrix (Gibbons, R. J.; J Dent Res 68, 750-760).
Many of the oral bacterial adhesins described in the art exhibit carbohydrate-specific binding and are often found on filamentous extensions (i.e., pili or fimbriae) which protrude from cell surfaces. These carbohydrate recognition structures, which are also referred to as lectins, mediate binding to host-derived or microbial-derived saccharide-containing structures on the teeth. Several different bacterial lectins have been described in the literature. By far, the lectins most commonly expressed by plaque bacteria are .beta.-galactoside-specific or "lactose sensitive" adhesins. The genera of bacteria which produce .beta.-galactoside-specific adhesins cover a diverse taxonomic range, including Actinomyces, Streptococcus, Porphyromonas, Fusobacterium, Haemophilus, Capnocytophaga, Veillonella, Prevotella, Staphylococcus, and Neisseria; these represent both primary and secondary colonizers of the teeth (Kollenbrander, P. E.; Crit Rev Microbiol 17:137-159). Kollenbrander notes that bacterial coaggregation plays an active role in formation of dental plaque and adherence of bacteria to epithelial cells in the oral econiche.
Most attempts to control plaque through anti-adhesion mechanisms have involved non-stereospecific inhibition of bacterial attachment to the teeth, usually with compositions containing surface-active polymers. For instance, G.B. Pat. No. 2,224,204A and U.S. Pat. No. 4,877,603 disclose oral compositions which include phosphonate-containing polymers that inhibit bacterial attachment to hydroxyapatite surfaces. Similarly, U.S. Pat. No. 4,663,202 discloses a method for treating surfaces with combinations of polymers which form barriers that retard bacterial adsorption.
With respect to blocking stereospecific interactions which mediate oral bacterial adherence, the use of mono- and oligosaccharides has been described, as inhibitors of lectin-mediated adhesion to human cells. For instance, abstract of U.S. Pat. No. 5,071,977 describes oligosaccharides isolated from S. sanguis which inhibit the build-up of adhesive dental plaque. Gaffar et al. (U.S. Pat. No. 5,002,759) disclose oligosaccharides containing either a galactose moiety (which may be .beta.-galactose) and/or a fucose moiety as agents in dentifrice preparations for inhibiting adherence of Streptococcus pyogenes to human epithelial cells. European Patent Application 184,121 discloses the use of galactose and/or lactose as anti-caries agents in foods, drinks, and pharmaceutical preparations. Neeser (U.S. Pat. Nos. 4,992,420 and 4,994,441) describes kappa-caseino-glycopeptide compounds and desialylated derivatives thereof (the derivatives contain .beta.-galactose groups) as inhibitors of in vitro adhesion by dental plaque bacteria to human erythrocytes.
Lynch et al. (U.S. Pat. No. 4,855,128) disclose polysaccharides such as xanthan gum, gum tragacanth, guar gum, gum karaya, chondroitin sulfate, polygalacturonic acid (pectin), sodium alginate and carrageenans of the kappa/lambda configuration as plaque-inhibitory agents which inhibit bacterial coaggregation; carrageenans of kappa/lambda configuration and chondroitin tin sulfate contain .beta.-galactose.
Stromberg et a). (J. Biol. Chem. 265,11251-11258) disclose that N-acetyl-galactosamine-B1,3-galactose-O-ethyl is an inhibitor of binding by Actinomyces viscosus and Actinomyces naeslundii to human erythrocytes. McIntire et al. (Infection and Immunity, vol. 41, No. 2, 848-850) have described O-glycosides of galactose-B1,3-N-acetyl- galactosamine, including phenyl, phenylethyl, and nitrophenyl derivatives, which inhibit coaggregation between Actinomyces sp. and Streptococcus sanguis; McIntire et al. note that the addition of aglycones increased the inhibitory activity significantly but not greatly. Stromberg et al. ("Synthetic Receptoranalogues Prevent Plaque Formation in Man", Abstracts of International Association for Dental Research Scandinavian Division, Helsinki, Aug. 22-24, 1991) disclose a study demonstrating the plaque inhibitory activity of GalNAc.beta.-3Gal.alpha.1-O-ethyl, which blocked adherence of Actinomyces strains 12104 and LY7. Clinical plaque strains were evaluated in a mouth rinse experiment including five human individuals. The study is said to demonstrate that receptor analogues such as GalNAc.beta.-3Gal.alpha.1-O-ethyl, may prove useful in future antiplaque therapy. The glycosides described by the Stromberg and McIntire references are expensive molecules and are different to synthesize and purify; hence, their practical utility is limited to the study of the stereospecificity of bacterial binding.
Saccharide derivatives distinct from the compounds employed in the present invention have been disclosed for applications in a non-dental environment.
Abstracts of Japanese Patent Applications 03112905 and 03112904 disclose the use, as antibacterials for preserving food and cosmetics, of 2-acetylamino-N-alkyl-glycosylamines and alkyl-glycosyl-amines represented by structures 1 and 2, respectively. Mardh et al. (U.S. Pat. Nos. 4,851,338) disclose the use of glycosides of structure 3 (which may contain .beta.-galactose) for diagnosing the presence of Staphylococcus bacteria and bacteria from the genus Bordatella pertussis. ##STR1##
Williams et al. ("A new class of Model Glycolipids: Synthesis, Characterization, and Interaction with Lectins", Archives of Biochemistry and Biophysics, vol. 195, No. 1 [1979], 145-151) disclose synthesis, characterization and lectin-glycolipid interaction of alkyl lactobionamides, cellobionamides and gentobionamides (all containing .beta.-D-glycosidic linkages). The compounds contained alkyl chain lengths of 12 or more carbon atoms. Williams et al. note that the glycolipids are able to compete with monosaccharides for the carbohydrate binding site. The ability of the glycolipids to act as surfactants is discussed. The Williams article describes aldobionamide-induced agglutination of solubilized plant lectins which are not cell-associated. By contrast, compositions according to the present invention are not aimed at attaining agglutination but are meant to inhibit adherent interactions mediated by cell-associated lectins on oral bacteria and/or inhibit bacterial growth.
A concurrently filed commonly assigned application Ser. No. 07/816,409, now abandoned, discloses the general utility of nonionic aldonamides, including lactobionamides, as surfactants in personal products and detergent formulations. Oral hygiene compositions according to the present invention may include surfactant molecules taught by the concurrently filed application, but the present invention is based, in part, on the discovery that specific aldobionamides containing a .beta.-galactosidic linkage, (e.g., lactobionamides) provide an antiplaque benefit by disrupting bacterial binding and/or acting as antimicrobial agents within the oral cavity.
Dental art heretofore has not made available a dentifrice composition containing antiplaque agents which are capable of delivering a surfactant benefit and/or antimicrobial activity and which also contain a .beta.-galactose targeting group. Furthermore, there is need for relatively cheap antiplaque .beta.-galactose-containing actives so that dentifrice compositions containing effective antiplaque agents may be produced on a commercial scale.
Accordingly, it is an object of the present invention to provide oral hygiene compositions which include specific aldobionamides containing a .beta.-galactosidic linkage as antiplaque agents.
It is another object of the present invention to provide oral hygiene compositions which contain effective yet commercially feasible antiplaque .beta.-galactose-containing compounds.
It is still another object of the invention to provide methods of inhibiting bacterial adhesion and/or bacterial growth in the oral cavity.
These and other objects of the invention will become more apparent from the detailed description and examples that follow.